Nitrite attenuates ischemia-reperfusion-induced microcirculatory alterations and mitochondrial dysfunction in the microvasculature of skeletal muscle

Plast Reconstr Surg. 2011 Oct;128(4):279e-287e. doi: 10.1097/PRS.0b013e3182268b9a.


Background: Recently, nitrite has been rediscovered as a physiologically relevant storage reservoir of nitric oxide in blood and it can readily be converted to nitric oxide under hypoxic and acidic conditions. In this study, the authors evaluated the therapeutic efficacy of nitrite on reperfusion-induced microcirculatory alterations and mitochondrial dysfunction in the microvasculature of skeletal muscle.

Methods: The authors used a vascular pedicle isolated rat cremaster model that underwent 4 hours of warm ischemia followed by 2 hours or 17 hours of reperfusion. At 5 minutes before reperfusion, normal saline, sodium nitrite (0.20 μM/minute/kg), or nitrite mixed with 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl (potassium salt) (0.2 mg/minute/kg) was infused into the microcirculation of ischemic cremaster by means of intraarterial infusion. Ischemia-reperfusion-induced microcirculatory alterations were measured after 2 hours of reperfusion. Microvasculature of the cremaster muscle including the vascular pedicle was harvested to determine the mitochondrial dysfunction. The blood concentration of methemoglobin was also measured to determine the toxicity of nitrite.

Results: The authors found that nitrite significantly attenuated ischemia-reperfusion-induced vasoconstriction, arteriole stagnation, and capillary no-reflow in the early phase of reperfusion and the depolarization of mitochondrial membrane potential and cytochrome c release in the late phase of reperfusion. Nitrite-induced protection was significantly blocked by a nitric oxide scavenger (potassium salt). The methemoglobin results showed that the doses of nitrite we used in the present study were safe.

Conclusion: The supplementation of a low dose of nitrite, directly into the microcirculation of ischemic muscle through local intraarterial infusion, significantly attenuated ischemia-reperfusion-induced microcirculatory alterations in vivo and mitochondrial dysfunction in vitro in the microvasculature of skeletal muscle.

Publication types

  • Comparative Study

MeSH terms

  • Analysis of Variance
  • Animals
  • Cytochromes c / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ischemia / drug therapy*
  • Male
  • Membrane Potentials
  • Methemoglobin / drug effects
  • Methemoglobin / metabolism
  • Microcirculation / drug effects
  • Mitochondria, Muscle / physiology*
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / physiopathology
  • Nitrites / pharmacology*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Reference Values
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / prevention & control*


  • Nitrites
  • Cytochromes c
  • Methemoglobin